Ex527 An Effective Sirt 1 Inhibitor
INTRODUCTION:
INTRODUCTION:
Sirt1, or Sirtuin1 is an NAD-dependent deacetylase enzyme and though its exact role is not fully understood yet, it is known to be implicated in gene regulation and many physiological conditions like stress, redox regulation, aging etc., to name a few. EX-527 is a highly specific Sirt1 inhibitor that has been used extensively for understanding the role of Sirt1 in various aspects of cell regulation.
EX-527: THE ORIGIN
EX-527 is a metabolically stable indole compound and it was identified as an effective Sirt1 inhibitor from a large number of compounds in a high throughput screening assay [1] on account of its high specificity against Sirt1. Since this knowledge came into the light more than 6 years before, EX-527 has been used in various research studies where Sirt1 has to be specifically inhibited leaving Sirt2 or Sirt3 unaffected.
RESEARCH STUDIES:
EX-527 has been used to recently consolidate the role of Sirt1 in deacetylating p53 to bring improvements in the case of nephrotoxicity which was induced in patients undergoing cispatin treatment [2], a validated part of cancer management regime. As the role of Sirt1 in the deacetylation of the tumor suppressor gene p53 was confirmed through blocking Sirt1 activity upon EX-527 [3], there are various research groups who want to work on elucidating the effect of EX-527 on different signaling cascades in cancer cells.
EX-527 "" AN EFFECTIVE SIRT1 INHIBITOR:
Before known for playing a role in p53 deacetylation to modulate its functions in p53 mutant cancer cells, EX-527 or 6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide was found to be a potent Sirt1 inhibitor in the course of virtual database screening [4]. Since Sirt1 is known to facilitate deacetylation of not only p53 but of nuclear transcription factor NF-kB too whose activation promotes cell proliferation and cell survival in cancer, a research study was conducted to see the mechanism with which EX-527 could reverse the effect of Sirt1 induced NF-kB inhibition. In adipocyte cell lines, EX-527 induced differentiation by removing Sirt1 inhibition of NF-kB, a possible way of making the adipocytes sensitive to insulin [5].
Similarly as Sirt1 has been implicated in the process of aging, EX-527 was used for inhibiting Sirt1 to validate its role in modulating cell senescence cycle to restore a young phenotype of cells [6] and removal of growth arrest.
CONCLUSION:
Since EX-527 has shown high specificity for Sirt1 inhibition leaving Sirt2 or 3 or any other Sirtuins unaffected at the dose required for Sirt1 inhibition, it is used as an effective strategy to validate the role of Sirtuin1 in various physiological and metabolic processes. If Sirt1 genes show any change in a gene profile expression study done for any disease conditions, EX-527 will be employed to confirm its role in the process thus warranting more studies with time.
REFERENCES:
1. Napper, A.D., Discovery of indoles as potent and selective inhibitors of the deacetylase SIRT1. J Med Chem., 2005. 48(25): p. 8045-54.
2. Kim, D.H., SIRT1 activation by resveratrol ameliorates cisplatin-induced renal injury through deacetylation of p53. Am J Physiol Renal Physiol., 2011. 301(2): p. 427-35.
3. Solomon, J.M.e.a., Inhibition of SIRT1 catalytic activity increases p53 acetylation but does not alter cell survival following DNA damage. Mol Cell Biol., 2006. 26(1): p. 28-38.
4. Huhtiniemi, T.e.a., Oxadiazole-carbonylaminothioureas as SIRT1 and SIRT2 inhibitors. J Med Chem., 2008. 51(15): p. 4377-80.
5. Nayagam, V.M.e.a., SIRT1 Modulating Compounds from High-Throughput Screening as Anti-Inflammatory and Insulin-Sensitizing Agents. J Biomol Screen, 2006. 11(8): p. 959-967.
6. Choi, H.R.e.a., Restoration of senescent human diploid fibroblasts by modulation of the extracellular matrix. Aging Cell, 2011. 10(1): p. 148-57.
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